Process for producing tricyclic ketone

ABSTRACT

In order to efficiently supply CPT, which is a starting compound of irinotecan hydrochloride and a variety of camptothecin derivatives, by a practical total synthesis, the invention provides a means of efficiently preparing a tricyclic ketone that corresponds to a CDE ring moiety of a camptothecin (CPT) skeleton.

TECHNICAL FIELD

The present invention relates to a process for preparing an intermediateinvolved in the synthesis of camptothecins having antitumor activity andto a novel formylation reagent used in the preparation process. Moreparticularly, it relates to an asymmetric synthetic method for acompound that is a starting material in preparing various types ofcamptothecin derivatives and has a tricyclic ketone moiety correspondingto the CDE ring moiety in the skeleton of camptothecins.

BACKGROUND ART

Camptothecin (hereinafter, referred to as CPT) isolated from the bark,root, fruit, leaf and the like of Camptotheca acuminata, which is nativeto China, is a pentacyclic alkaloid, and is known to exhibit antitumoractivity by inhibiting nucleic acid synthesis. On the other hand, it hasbeen reported that camptothecin derivatives induce side effects such asdiarrhea (‘Gan to Kagakuryoho’ (Cancer & Chemotherapy) 17, p 115-120,1990) and disorders of the digestive organs; because of thesesituations, various types of derivatives have been studied with theobject of reducing the toxicity, increasing the effect, etc.

The present inventors have already reported, as a compound havingsuppressed toxicity compared with CPT,7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecinhydrochloride trihydrate (hereinafter, referred to as CPT-11), which isa water-soluble semisynthetic derivative of CPT and is currently widelyused as an antitumor agent (generic name; irinotecan hydrochloride).

Camptothecins such as CPT-11 may be obtained by chemical modification ofCPT obtained from natural materials.

However, since the amount of CPT obtained from a natural material suchas Camptotheca acuminata, which is a raw material, is extremely small,it is anticipated that it will become difficult to supply a sufficientamount of CPT because of a highly increased demand of CPT-11.Furthermore, preparation methods by total synthesis have been studied,but it is not practical at present.

The present inventors have synthesized4-iodo-2-methoxy-6-trimethylsilylpyridine-3-carbaldehyde (hereinafter,referred to as compound (b)), which is an intermediate in the synthesisof a tricyclic ketone moiety corresponding to the CDE ring moiety ofCPTs, by the scheme below (Patent Publication 1),

however, there is a possibility that it might become difficult to obtain2-(dimethylamino)ethyl chloride, which is a starting material in thepreparation of N-methyl-N-[2-(dimethylamino)ethyl]formamide (FLM) usedin this method in the future as it can serve as a starting material inthe preparation of a chemical weapon.

On the other hand, alkoxyalkylformamide (formula I) analogs used asformylation reagents of the present invention have been reported (PatentPublications 2 and 3), but these have only been used as startingmaterials for 6-aminopenicillanic acid or disclosed as a by-product inelectrosynthesizing a butanetetracarboxylic acid derivative, and therehas been no description at all of their use as formylation reagents.

[Patent Publication 1] WO 02/066416

[Patent Publication 2] JP, B, 51-8955

[Patent Publication 3] JP, A, 2004-514786

DISCLOSURE OF INVENTION Problems to be Solved by the Invention

It is therefore an object of the present invention to efficiently supplyCPT, which is a starting compound for irinotecan hydrochloride and forvarious types of camptothecin derivatives, and camptothecin analogs suchas 7-ethyl-10-hydroxycamptothecin (SN-38), which is an importantintermediate for the synthesis of irinotecan hydrochloride by practicaltotal synthesis.

Means for Solving the Problems

In order to solve the above-mentioned problems, the present inventorshave developed novel formylation reagents for a methoxypyridinederivative used in preparation of(S)-4-ethyl-3,4,6,7,8,10-hexahydro-4-hydroxy-1H-pyrano[3,4-f]indolizin-3,6,10-trione(hereinafter, referred to as compound (k)), which corresponds to the CDEring moiety of the CPT skeleton, for the purpose of improving thepreparation process, and have found that use of the formylation reagentsenables formylation of the methoxypyridine derivative and subsequentiodination to be carried out in high yield, and the present inventionhas thus been accomplished.

Namely, the present invention relates to a process for preparing atricyclic ketone (k), represented by the formula below, for synthesizingcamptothecin analogs

(wherein Me denotes a methyl group, Pr denotes a propyl group, and t-Budenotes a t-butyl group),

the process comprising a step (1) of mixing the above2-methoxy-6-(trimethylsilyl)pyridine (hereinafter, referred to ascompound (a)), a compound represented by formula (I) below

(wherein R and R′ are independently alkyl having 1 or 2 carbons, and nis an integer of 1 to 3) and a lithiation reagent, and subsequentlymixing with an iodination reagent to give compound (b).

Furthermore, the present invention relates to the process for preparingthe tricyclic ketone (k), the process further comprising a step (2) ofmixing and stirring in a solvent at least one type of palladium catalystselected from palladium (II) chloride, palladium (II) acetate,palladium-carbon, palladium hydroxide-carbon, bis(acetonitrile)palladium(II) dichloride, bis(benzonitrile)palladium (II) dichloride, andbis(dibenzylideneacetone)palladium (0),3-(2-butenyloxymethyl)-4-iodo-2-methoxy-6-(trimethylsilyl)pyridine(hereinafter, referred to as compound (c)), a base, and a quaternaryammonium salt to give4-ethyl-8-methoxy-6-trimethylsilyl-1H-pyrano[3,4-c]pyridine(hereinafter, referred to as compound (d)).

The present invention relates to the process for preparing the tricyclicketone (k), wherein in step (1) the compound represented by formula (I)in which n is 2 is used.

Furthermore, the present invention relates to the process for preparingthe tricyclic ketone (k), wherein in step (1) the lithiation reagent isn-butyllithium.

Moreover, the present invention relates to the process for preparing thetricyclic ketone (k), wherein in step (2) the solvent is awater-containing solvent.

The present invention also relates to the process for preparing thetricyclic ketone (k), wherein in step (2) the solvent is a mixture of anitrile-type organic solvent and water.

Furthermore, the present invention relates to the process for preparingthe tricyclic ketone (k), wherein in step (2) the solvent is a mixtureof an ether-type organic solvent, a nitrile-type organic solvent, andwater.

The present invention relates to the use of the tricyclic ketone (k)obtained by the above-mentioned process in the preparation ofcamptothecin analogs.

Furthermore, the present invention relates to a process for synthesizingcamptothecin analogs, the process involving reacting the tricyclicketone (k) obtained by the above-mentioned process with2′-amino-5′-hydroxypropiophenone.

Moreover, the present invention relates to a process for preparingformylated methoxypyridine derivatives by reacting methoxypyridinederivatives with a compound (alkoxyalkylformamide) represented byformula (I)

(wherein R and R′ are independently alkyl having 1 or 2 carbons, and nis an integer of 1 to 3).

The present invention relates to the process for preparing formylatedmethoxypyridine derivatives, wherein a compound of formula (I) in whichn is 2 is used. Furthermore, the present invention relates to theprocess for preparing the formylated methoxypyridine derivatives,wherein it is carried out in the presence of n-butyllithium.

Moreover, the present invention relates to the process for preparing theformylated methoxypyridine derivatives, wherein it is a process forpreparing a compound represented by formula (II),

(wherein R is a halogen, alkyl, or trimethylsilyl group, and R′is ahalogen, alkyl, trimethylsilyl, or thioalkyl group), and an orthoposition to a formyl group introduced by the above-mentioned preparationprocess is substituted with an electrophile.

Furthermore, the present invention relates to alkoxyalkylformamidesrepresented by formula (I)

(wherein R and R′ are independently alkyl having 1 or 2 carbons and n isan integer of 1 to 3, but excluding one in which n is 1 and R and R′ areboth methyl and one in which n is 2 and R and R′ are both ethyl).

EFFECTS OF THE INVENTION

Not only can the alkoxyalkylformamides [formula (I)] of the presentinvention be used effectively as formylation reagents for amethoxypyridine derivative, but it is also possible to efficientlysupply the tricyclic ketone (k) as an intermediate of camptothecinanalogs.

Furthermore, by use of the present invention, the endo/exo ratio ofcompound (d), which is an intermediate for the tricyclic ketone (k), canbe increased effectively. By selecting as a palladium catalyst for theprocess at least one type from palladium (II) chloride, palladium (II)acetate, palladium-carbon, palladium hydroxide-carbon,bis(acetonitrile)palladium (II) dichloride, bis(benzonitrile)palladium(II) dichloride, and bis(dibenzylideneacetone)palladium (0), theendo/exo ratio and the yield can be improved.

BEST MODE FOR CARRYING OUT THE INVENTION

Preparation of the Tricyclic Ketone (k) is Carried out via the syntheticroute below.

In the formula, Me denotes a methyl group, Pr denotes a propyl group,and t-Bu denotes a t-butyl group. With regard to compound (a), whichserves as a starting compound in the above-mentioned synthetic route, itmay be synthesized by the Curran route (Josien, H.; Ko, S. B.; Bom, D.;Curran, D. P., Chem. Eur. J. 1998, 4, 67-83, “A General SyntheticApproach to the (20S)-Camptothecin Family of Antitumor Agents by aRegiocontrolled Cascade Radical Cyclization of Aryl Isonitriles”),obtained by chemical modifications of compound (a) analogs, or obtainedby isolation and purification from various types of natural materialsand the like, or it may be a natural material itself containing compound(a).

A preferred process for synthesizing the tricyclic ketone (k) in theabove-mentioned synthetic route comprises step (i) or steps (i) and (iv)among the steps below:

(i) a step of synthesizing compound (b) by mixing2-methoxy-6-trimethylsilylpyridine (compound (a)) with a lithiationreagent, an alkoxyalkylformamide [formula (I)], and an iodinationreagent,(ii) a step of synthesizing compound (c) by mixing compound (b) withcrotyl alcohol, triethylsilane, and an acid, and reacting the mixturewithout a solvent,(iii) a step of obtaining compound (b) by mixing4-iodo-3-hydroxymethyl-2-methoxy-6-(trimethylsilyl)pyridine(hereinafter, referred to as compound (c′)), which is a by-product instep (ii), with an oxidizing agent and in some cases a base,(iv) a step of synthesizing compound (d) by mixing and stirring compound(c) in the presence of a palladium catalyst, a base, and a quaternaryammonium salt in a solvent,(v) a step of synthesizing(S)-4-ethyl-3,4-dihydro-8-methoxy-6-trimethylsilyl-1H-pyrano[3,4-c]pyridine-3,4-diol(hereinafter, referred to as compound (e)) from compound (d) with anosmium catalyst, a co-oxidizing agent, a base, an asymmetric reagent,and methanesulfonamide,(vi) a step of synthesizing(S)-4-ethyl-3,4-dihydro-4-hydroxy-8-methoxy-6-trimethylsilyl-1H-pyrano[3,4-c]pyridin-3-one(hereinafter, referred to as compound (f)) by mixing compound (e) with abase and iodine, and heating the mixture in an alcohol-water mixtureunder reflux,(vii) a step of synthesizing(S)-4-ethyl-3,4-dihydro-4-hydroxy-6-iodo-8-methoxy-1H-pyrano[3,4-c]pyridin-3-one(hereinafter, referred to as compound (g)) by mixing compound (f) with adesilylation-iodination reagent,(viii) a step of chemically purifying compound (g) by adding a basicaqueous solution such as a sodium hydroxide solution to make thesolution alkaline, washing with an organic solvent such as chloroform,subsequently making the aqueous layer acidic, and extracting with anorganic solvent such as chloroform,(ix) a step of optically purifying compound (g) by dissolving compound(g) in a high polarity solvent such as chloroform, adding a low polaritysolvent such as n-hexane, filtering the resulting precipitate, andconcentrating the filtrate,(x) a step of obtaining(S)-4-ethyl-3,4-dihydro-4-hydroxy-8-methoxy-3-oxo-1H-pyrano[3,4-c]pyridine-6-carboxylicacid propyl ester (hereinafter, referred to as compound (h)) by mixingcompound (g) with a palladium catalyst and a base and reacting themixture in 1-propanol under a carbon monoxide atmosphere,(xi) a step of synthesizing(S)-4-ethyl-3,4,7,8-tetrahydro-4-hydroxy-3,8-dioxo-1H-pyrano[3,4-c]pyridine-6-carboxylicacid propyl ester (hereinafter, referred to as compound (i)) by reactingcompound (h) with a demethylation reagent at room temperature, and(xii) a step of synthesizing(S)-4-ethyl-3,4,8,10-tetrahydro-4,6-dihydroxy-3,10-dioxo-1H-pyrano[3,4-f]indolizine-7-carboxylicacid 1,1-dimethylethyl ester (hereinafter, referred to as compound (j))by reacting compound (i) with t-butyl acrylate and a base. Compound (k)may be synthesized from compound (j) via the above-mentioned Curranroute.

Furthermore, (xiii) in a step of obtaining SN-38 from compound (k) and2′-amino-5′-hydroxypropiophenone, SN-38 can favorably be obtained by thereaction under an inert gas atmosphere.

The above-mentioned 13 steps are now explained in further detail.

In (i), compound (a) is dissolved in a solvent, and a lithiationreagent, a formylation reagent, and an iodination reagent are added tothe solution and it is stirred to give compound (b). As the solvent,tetrahydrofuran (THF), diethyl ether, toluene, hexane, heptane and thelike may be used, and from the viewpoint of solubility and reactivityTHF is particularly preferable.

As the lithiation reagent, any one may suitably be used if it isconventionally used. Specific examples of the lithiation reagent includen-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide(LDA), and lithium bis(trimethylsilyl)amide (LiHMDS), and particularlyfrom the viewpoint of ease of handling and reactivity, n-butyllithiummay suitably be used.

The amount of lithiation reagent may be determined appropriatelyaccording to the reagent, and in case that n-butyllithium is used, it isused at 0.5 to 10 equivalents relative to compound (a), preferably 1 to5 equivalents.

The reaction temperature for lithiation is a constant temperature in therange of −78° C. to 25° C., preferably −78° C. to 0° C., particularlypreferably −30° C. to 0° C.

Specific examples of the formylation reagent used in the presentinvention include N-methoxymethyl-N-methylformamide (FMM),N-methoxyethyl-N-methylformamide (FMO), N-ethoxyethyl-N-methylformamide(FEO), N-methoxyethyl-N-ethylformamide (FEA),N-ethoxyethyl-N-ethylformamide (FEE), andN-ethoxypropyl-N-methylformamide (FEP), and when taking intoconsideration the subsequent iodination, FMO, FEO, FEA, or FEE maysuitably be used.

With regard to the amount of formylation reagent, in case that FEO isused, it is 1 to 10 equivalents relative to compound (a), preferably 1to 3 equivalents.

The reaction temperature for formylation is a constant temperature inthe range of −78° C. to 25° C., preferably −78° C. to 0° C.,particularly preferably −30° C. to 0° C.

As the iodination reagent, iodine, N-iodosuccinimide (NIS),1,2-diiodoethane and the like may be used, and from the viewpoint ofcost and reactivity iodine is particularly preferable.

The amount of iodination reagent is 1 to 10 equivalents relative tocompound (a), preferably 1 to 5 equivalents.

The reaction temperature for iodination is in the range of −78° C. to25° C., preferably −78° C. to 0° C. The reaction may be carried out at aconstant temperature or may be carried out while raising the temperaturewithin these ranges.

In (ii), compound (c) is obtained by adding crotyl alcohol,triethylsilane, and an acid to compound (b) and stirring withoutemploying a solvent.

The amount of crotyl alcohol is 1 to 10 equivalents relative to compound(b), preferably 2 to 5-equivalents.

The amount of triethylsilane is 1 to 10 equivalents relative to compound(b), preferably 1 to 4 equivalents.

As the acid, trifluoroacetic acid (TFA), sulfuric acid, methanesulfonicacid, hydrochloric acid and the like may be used, and from the viewpointof reactivity TFA is particularly preferable.

With regard to the amount of acid, in case that TFA is used, it is 1 to20 equivalents relative to compound (b), preferably 5 to 15 equivalents.

In (iii), compound (b) is obtained by dissolving compound (c′), which isa by-product in (ii), in a solvent, adding an oxidizing agent, and insome cases a base, and stirring.

As the solvent, any one may suitably be used if it is conventionallyused. Examples of such a solvent include dichloromethane, chloroform,acetonitrile, toluene, and n-hexane, and from the viewpoint ofreactivity toluene and n-hexane are particularly preferable.

Examples of the oxidizing agent include manganese dioxide, Dess-Martinreagent (Dess-Martin Periodinane), Jones reagent (Na₂Cr₂O₇—H₂SO₄), PCC,PDC, DMSO-oxalyl chloride-triethylamine (Swern oxidation), and aTEMPO-hypochlorite; the TEMPO-hypochlorite is particularly preferable,and TEMPO-sodium hypochlorite is more preferable.

With regard to the amount of oxidizing agent, for example, in the caseof TEMPO-sodium hypochlorite, TEMPO is used at 0.001 to 0.1 equivalentsrelative to compound (c′), preferably 0.005 to 0.02 equivalents. Sodiumhypochlorite is used at 1 to 5 equivalents, preferably 1 to 2equivalents.

As the base, any one may suitably be used if it is conventionally used.Examples of such a base include sodium hydrogen carbonate, sodiumcarbonate, potassium carbonate, calcium carbonate, sodium hydroxide,potassium hydroxide, calcium hydroxide, and triethylamine, and sodiumhydrogen carbonate is particularly preferable.

With regard to the amount of base, for example, in the case of sodiumhydrogen carbonate, sodium hydrogen carbonate is 1 to 10 equivalentsrelative to compound (c′), preferably 2 to 4 equivalents. With regard tothe reaction temperature, in case that TEMPO-sodium hypochlorite is usedas the oxidizing agent, it is in the range of −20° C. to 30° C., and inorder to particularly suppress a side reaction it is preferably −20° C.to 10° C.

Furthermore, with regard to the reaction time, in case that TEMPO-sodiumhypochlorite is used as the oxidizing agent, it is in the range of 0.1to 10 hours, preferably 0.5 to 5 hours.

In (iv), compound (d) is obtained by dissolving compound (c) in asolvent, adding a palladium catalyst, a base, and a quaternary ammoniumsalt, and heating under reflux.

As the solvent, a nitrile-type solvent such as acetonitrile orpropionitrile, an ether-type solvent such as tetrahydrofuran (THF),diisopropyl ether (IPE), diethyl ether, or 1,2-dimethoxyethane, toluene,water and the like may be used. Particularly from the viewpoint ofreactivity a mixture in which any of an ether-type solvent, anitrile-type solvent, and water are combined is preferable, a mixture ofIPE, acetonitrile and water is particularly preferable, and a mixture ofacetonitrile and water is more particularly preferable.

As the palladium catalyst, palladium (II) chloride, palladium (II)acetate, palladium-carbon, palladium hydroxide-carbon,bis(acetonitrile)palladium (II) dichloride, bis(benzonitrile)palladium(II) dichloride, bis(dibenzylideneacetone)palladium (0) and the like maysuitably be used, and from the viewpoint of reactivity palladium (II)chloride is particularly preferable.

The amount of palladium catalyst is 0.01 to 1 equivalents relative tocompound (c), preferably 0.05 to 0.2 equivalents.

As the base, any one may suitably be used if it is conventionally used.Examples of such a base include sodium carbonate, potassium carbonate,calcium carbonate, cesium carbonate, triethylamine (TEA),N,N-diisopropylethylamine (DIPEA), sodium hydroxide, and potassiumhydroxide, and TEA and DIPEA may be used particularly suitably.

With regard to the amount of base, for example, in the case of TEA, itis 1 to 20 equivalents relative to compound (c), preferably 5 to 10equivalents.

As the quaternary ammonium salt, any one may suitably be used if it isconventionally used. Examples of such quaternary ammonium salts includea tetrabutylammonium halide and a benzyltriethylammonium halide, andtetrabutylammonium bromide is particularly preferable.

With regard to the amount of quaternary ammonium salt, for example, inthe case of tetrabutylammonium bromide, it is 0.1 to 3 equivalentsrelative to compound (c), preferably 0.5 to 1.5 equivalents.

Furthermore, with regard to the reaction time, in case that a mixture ofacetonitrile, IPE and water is used, it is in the range of 0.1 to 10hours, preferably 0.5 to 5 hours.

In (v), compound (e) is obtained by dissolving compound (d) in a mixtureof alcohol and water, adding an osmium catalyst, a co-oxidizing agent,an asymmetric reagent, a base, and methanesulfonamide, and stirring.

Examples of the alcohol include methanol, ethanol, 1-propanol,2-propanol (IPA), 1-butanol, 2-butanol, and t-butyl alcohol. From theviewpoint of reactivity t-butyl alcohol is particularly preferable.

As the osmium catalyst, osmium tetraoxide, potassium osmate (VI) and thelike may be used suitably, and from the viewpoint of ease of handlingpotassium osmate (VI) is particularly preferable.

The amount of osmium catalyst is 0.001 to 0.1 equivalents relative tocompound (d), preferably 0.002 to 0.01 equivalents.

As the co-oxidizing agent, potassium hexacyanoferrate (III),4-methylmorpholine N-oxide (NMO), etc. may be used suitably, and fromthe viewpoint of reactivity potassium hexacyanoferrate (III) isparticularly preferable.

With regard to the amount of co-oxidizing agent, for example, in thecase of potassium hexacyanoferrate (III), it is 1 to 10 equivalentsrelative to compound (d), preferably 2 to 5 equivalents.

Examples of the asymmetric reagent include (DHQD)₂PYR, (DHQD)₂PHAL, and(DHQD)₂AQN, and from the viewpoint of optical yield (DHQD)₂PYR isparticularly preferable.

With regard to the amount of asymmetric reagent, for example, in thecase of (DHQD)₂PYR, it is 0.005 to 0.1 equivalents relative to compound(d), preferably 0.01 to 0.05 equivalents.

As the base, sodium carbonate, potassium carbonate, calcium carbonate,cesium carbonate, sodium hydroxide, potassium hydroxide and the like maybe used, and from the viewpoint of reactivity potassium carbonate isparticularly preferable.

With regard to the amount of base, for example, in the case of potassiumcarbonate, it is 1 to 20 equivalents relative to compound (d),preferably 4 to 10 equivalents.

The amount of methanesulfonamide is 0.1 to 5 equivalents relative tocompound (d), preferably 0.5 to 2 equivalents.

The reaction temperature is in the range of −20° C. to 30° C.,preferably −10° C. to 10° C.

In (vi), compound (f) is obtained by dissolving compound (e) in asolvent, adding a base and iodine, and heating under reflux.

Examples of the solvent include methanol, ethanol, 1-propanol,2-propanol (IPA), and water, and from the viewpoint of reactivity amixture of methanol and water is particularly preferable.

As the base, a conventionally used base may be used suitably. Examplesof such a base include sodium carbonate, potassium carbonate, calciumcarbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide,and calcium carbonate is particularly preferable.

With regard to the amount of base, for example, in the case of calciumcarbonate, it is 1 to 10 equivalents relative to compound (e),preferably 2 to 5 equivalents.

With regard to the amount of iodine, it is 1 to 10 equivalents relativeto compound (e), preferably 3 to 5 equivalents.

Furthermore, the reaction time is in the range of 0.5 to 20 hours, morepreferably 1 to 5 hours.

In (vii), compound (g) is obtained by dissolving compound (f) in asolvent, and reacting in the presence of iodine-silver trifluoroacetate(hereinafter, referred to as I₂—CF₃COOAg) or N-chlorosuccinimide-sodiumiodide (hereinafter, referred to as NCS-NaI).

With regard to the solvent, in the case of I₂—CF₃COOAg, dichloromethane,carbon tetrachloride, chloroform and the like are suitable, anddichloromethane is particularly preferable. In the case of NCS-NaI,acetic acid, acetonitrile and the like may be used, and from theviewpoint of reactivity acetic acid is particularly preferable.

With regard to the amount of I₂—CF₃COOAg, I₂ is 1 to 10 equivalentsrelative to compound (f), preferably 2 to 4 equivalents. CF₃COOAg is 1to 10 equivalents, preferably 2 to 4 equivalents.

With regard to the amount of NCS-NaI, NCS is 1 to 20 equivalentsrelative to compound (f), preferably 5 to 8 equivalents. NaI is 1 to 20equivalents, preferably 5 to 8 equivalents.

With regard to the temperature during the reaction, in case thatI₂—CF₃COOAg is used, it is 10° C. to 60° C., preferably 20° C. to 40° C.In case that NCS-NaI is used, it is 20° C. to the reflux temperature,preferably 50° C. to 80° C.

Furthermore, the reaction time is in the range of 5 to 48 hours,preferably 15 to 24 hours.

In (viii), for example, by adding to compound (g) a basic solvent suchas a 0.2 N aqueous solution of sodium hydroxide and stirring, compound(g) becomes a lactone ring-opened form (compound (l):

(wherein Me denotes a methyl group, Et denotes an ethyl group, X denotesan alkali metal or an alkaline earth metal, and n denotes 1 or 2)), anddissolves in the basic aqueous solution. When this solution is washedwith an organic solvent, neutral and basic materials move to the organiclayer. After the organic layer is separated, the aqueous layer is madeacidic using an acid and extracted with an organic solvent, thusrecovering compound (g) with good purity.

The concentration of basic solvent is in the range of 0.01 to 5 N,preferably 0.1 to 1 N. It is more preferably 0.2 to 0.5 N.

Examples of the base include potassium hydroxide, calcium hydroxide,sodium hydroxide, potassium carbonate, and sodium carbonate, and sodiumhydroxide is particularly preferable.

As the organic solvent, any one may suitably be used if it isconventionally used. Examples of such a solvent include dichloromethane,chloroform, ethyl acetate, toluene, diethyl ether, and diisopropylether, and dichloromethane and chloroform are particularly preferable.

Examples of the acid include hydrochloric acid, sulfuric acid, nitricacid, acetic acid, phosphoric acid, and trifluoroacetic acid, andhydrochloric acid is particularly preferable.

In (ix), when compound (g) is dissolved in a high polarity solvent and alow polarity solvent is added, crystals are precipitated. The crystalsare filtered off, and the filtrate is concentrated and dried underreduced pressure. The resulting crystals are racemic, and a moreoptically purified compound (g) is obtained as a residue.

As the high polarity solvent, chloroform, dichloromethane, ethylacetate, methanol, ethanol, propanol and the like may be used, andchloroform is particularly preferable. With regard to the amount of highpolarity solvent, for example, in the case of chloroform, it is in therange of 0.5 to 10 mL relative to 1 g of compound (g), preferably 1 to 5mL, particularly preferably 3 to 5 mL.

Examples of the low polarity solvent include n-hexane, n-heptane, anddiethyl ether, and n-hexane is particularly preferable.

With regard to the high polarity solvent:low polarity solvent ratio, forexample, in the case of chloroform:n-hexane, it is in the range of 10:1to 1:20, preferably 5:1 to 1:5.

The temperature of the crystallization procedure is preferably nogreater than 30° C., particularly preferably 0° C. to 30° C.

In (x), compound (h) is obtained by dissolving compound (g) in1-propanol, adding a palladium catalyst and a base, and reacting underan atmosphere of carbon monoxide gas.

As the palladium catalyst, palladium (II) acetate,tetrakis(triphenylphosphine)palladium (0),dichlorobis(triphenylphosphine)palladium(II), palladium (II) chlorideand the like may suitably be used, and from the viewpoint of reactivitypalladium (II) acetate is particularly preferable.

The amount of palladium catalyst is 0.005 to 0.5 equivalents relative tocompound (g), preferably 0.01 to 0.1 equivalents.

As the base, any one may suitably be used if it is conventionally used.Examples of such a base include sodium carbonate, potassium carbonate,calcium carbonate, cesium carbonate, triethylamine (TEA),N,N-diisopropylethylamine (DIPEA), sodium hydroxide, and potassiumhydroxide, and potassium carbonate, TEA, and DIPEA are particularlysuitably used. With regard to the amount of base, for example, in thecase of potassium carbonate, it is 1 to 20 equivalents relative tocompound (g), preferably 4 to 10 equivalents.

The reaction temperature is in the range of 20° C. to the refluxtemperature, preferably 50° C. to the reflux temperature.

In (xi), compound (i) is obtained by dissolving compound (h) in asolvent, adding a demethylation reagent, and reacting at roomtemperature.

As the solvent, acetonitrile, chloroform, dichloromethane, toluene andthe like may be used, and acetonitrile is particularly preferable.

Examples of the demethylation reagent includechlorotrimethylsilane-sodium iodide, iodotrimethylsilane, hydroiodicacid, and hydrobromic acid, and from the viewpoint of reactivitychlorotrimethylsilane-sodium iodide is particularly preferable.

With regard to the amount of demethylation reagent, for example, in thecase of chlorotrimethylsilane-sodium iodide, chlorotrimethylsilane andsodium iodide are both in the range of 1 to 10 equivalents relative tocompound (h), preferably 2 to 5 equivalents.

In (xii), compound (i) is dissolved in a solvent, a base is added, andit is stirred under an inert gas. t-Butyl acrylate is added dropwise tothe resulting mixture, and it is stirred under an inert gas, thus givingcompound (j).

With regard to the solvent, dimethyl sulfoxide (DMSO),N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) and the likemay be used suitably, and from the viewpoint of reactivity DMSO isparticularly preferable.

As the base, potassium carbonate, sodium carbonate, sodium hydroxide,potassium hydroxide and the like may be used, and potassium carbonate isparticularly preferable.

With regard to the amount of base added, for example, in the case ofpotassium carbonate, it is 1 to 20 equivalents relative to compound (i),preferably 2 to 5 equivalents.

As the inert gas, a noble gas such as argon, helium, neon, krypton,xenon, or radon or any gas that has low reactivity such as nitrogen maybe used, and in terms of cost argon and nitrogen are preferable.

The amount of t-butyl acrylate is 1 to 20 equivalents relative tocompound (i), preferably 8 to 12 equivalents.

The reaction temperature is in the range of 20° C. to 80° C., preferably40° C. to 60° C.

Furthermore, the reaction time is 5 to 48 hours, and in order to preventdecomposition of the compound (j) thus formed, it is particularlypreferably less than 24 hours. Compound (k) may be synthesized by theabove-mentioned Curran route from compound (j).

In (xiii), SN-38 is obtained by dissolving compound (k) and2′-amino-5′-propiophenone in a solvent, adding an acid, and heating andstirring under an atmosphere of an inert gas.

As the solvent, toluene, acetic acid and the like may be used suitably,and a mixture of toluene and acetic acid is particularly preferable.

As the inert gas, a noble gas such as argon, helium, neon, krypton,xenon, or radon or any gas that has low reactivity such as nitrogen maybe used, and in terms of cost argon and nitrogen are preferable.

As the acid, toluenesulfonic acid, methanesulfonic acid, trifluoroaceticacid and the like may be used, and from the viewpoint of reactivitytoluenesulfonic acid is particularly preferable.

With regard to the amount of acid, for example, in the case oftoluenesulfonic acid, it is 1 to 100 mg relative to 1 g of compound (k),preferably 10 to 30 mg.

The amount of 2′-amino-5′-propiophenone is 1 to 3 equivalents relativeto compound (k), preferably 1 to 1.5 equivalents.

The reaction temperature is in the range of 50° C. to the refluxtemperature, preferably in the range of 80° C. to the refluxtemperature.

The alkoxyalkylformamide [formula (I)] of the present invention is notonly suitable for formylation of compound (a) but may also be used informylation of general methoxypyridine derivatives, and it is possibleto prepare formylated methoxypyridine derivatives in high yield.

Examples of methoxypyridine derivatives that can be formylated with thealkoxyalkylformamide [formula (I)] of the present invention include, inaddition to compound (a), 2-methoxypyridine, 2-chloro-6-methoxypyridine,2-alkyl-6-methoxypyridine, 2-methoxy-5-(trimethylsilyl)pyridine,5-chloro-2-methoxypyridine, and 5-alkyl-2-methoxypyridine. The termalkyl referred to here means lower alkyl having 1 to 5 carbons.

Furthermore, after formylation of a methoxypyridine derivative using thealkoxyalkylformamide [formula (I)] of the present invention, it ispossible, using various types of electrophile, to selectively add asubstituent to the ortho position of the formyl group that has beenintroduced.

Examples of electrophiles include, in addition to iodine, methyl iodide,chlorotrimethylsilane, hexachloroethane, tetrabromomethane, anddimethyldisulfide.

The present invention is illustrated further in detail below byreference to Examples, but the present invention is not limited thereto.

EXAMPLES Example 1

Synthesis of compound (b) from compound (a) was studied with thealkoxyalkylformamides [formula (I)] of the present invention.

In a reaction vessel filled with nitrogen gas or argon gas, compound (a)(1.00 g, 5.52 mmol) was dissolved in dry tetrahydrofuran (about 13 mL)and cooled to around −30° C. to −15° C. n-Butyllithium (1.6 mol/Ln-hexane solution; 4.8 mL, 7.73 mmol, 1.4 equivalents) was addeddropwise to the resulting solution, and stirred at the same temperaturefor 1 hour. Subsequently, an alkoxyalkylformamide (1.2 equivalents)shown in Table 2 was added dropwise, and the mixture was stirred at thesame temperature for 2 hours. Part of the reaction solution was sampled,quenched with water, and then extracted with ethyl acetate. Part of theresulting organic layer was injected into an HPLC, and the progress ofthe reaction was checked. The HPLC operating conditions were the same asin a quantitative determination method for compound (b).

n-Butyllithium (1.6 mol/L n-hexane solution; 7.0 mL, 11.0 mmol, 2.0equivalents) was added dropwise to the resulting mixture and stirred ataround −30° C. to −15° C. for 3 hours. Subsequently, a drytetrahydrofuran solution (5.5 mL) of iodine (3.64 g, 14.4 mmol, 2.6equivalents) was added dropwise at around −60° C. to −45° C., and themixture was stirred at the same temperature for 30 minutes.

An aqueous solution of sodium sulfite (appropriate amount, until thecolor of iodine disappeared) and n-hexane (appropriate amount) wereadded into the resulting mixture and stirred, the organic layer was thenseparated and concentrated to dryness, and the resulting residue wasanalyzed by an HPLC method. The results are given in Table 1.

Quantitative Determination Method for Compound (b)

About 20 mg of a test sample was precisely weighed and dissolved inacetonitrile to accurately make 100 mL, thus giving a sample solution.About 20 mg of standard compound (b) (column purified product: knownpurity) was precisely weighed and dissolved in acetonitrile toaccurately make 100 mL, thus giving a standard solution. 10 μL each ofthe sample and the standard solution were tested by a liquidchromatographic method in accordance with a Japanese PharmacopeiaGeneral Test Procedure under the operating conditions below. The peakareas of PM obtained from the sample and from the standard solution weremeasured and the content was determined by the formula below.

Content (%) of compound (b)=At×Ws×P/(As×Wt)

At: peak area of PM obtained from sample solution

As: peak area of PM obtained from standard solution

Wt: sampling weight of test PM (mg)

Ws: sampling weight of standard PM (mg)

P: purity of standard PM (%)

HPLC Operating Conditions Column: Inertsil ODS-2, 4.6 mm ID×150 mm

Mobile phase: MeCN-0.01 mol/LKH₂PO₄ mixture (5:1)Measurement wavelength: 254 nmFlow rate: about 1 mL/minMeasurement temperature: constant temperature at around 40° C.

TABLE 1 Formylation %¹⁾ Iodination %¹⁾ Run Reagent MTPC PM IMTP Yield²⁾% 1 FLM 89.9 59.7 6.5 55 2 FMM 74.8 5.8 15.2 —³⁾ 3 FMO 81.9 55.3 10.1 494 FEO 85.3 61.4 5.4 52 5 FEA 82.0 57.7 7.8 52 6 FEE 82.8 58.2 5.0 52 7FEP 83.6 29.0 6.1 —³⁾ ¹⁾HPLC area percentage ²⁾Calculated based onquantitative determination by HPLC ³⁾Not calculated

In Table 1 above, ‘FLM’ in run 1 meansN-methyl-N-[2-(dimethylamino)ethyl]formamide, which is conventionallyused as a formylation reagent, and the abbreviations for the reagents ofrun 2 to run 7 mean the alkoxyalkylformamides described in Table 2below.

TABLE 2 Alkoxyalkylformamides

Compound name n R R′ FMM 1 Me Me FMO 2 Me Me FEO 2 Me Et FEA 2 Et Me FEE2 Et Et FEP 3 Me Et

As is clear from the results, the alkoxyalkylformamides of the presentinvention can be used effectively as a formylation reagent, and exhibitsa performance that is not inferior to the conventional FLM.

Example 2

A reaction was examined with the alkoxyalkylformamide [formula (I)] ataround −15° C. to 0° C.

n-Butyllithium (1.6 M in n-hexane, 4.8 mL, 5.52×1.4 mmol) was addeddropwise to a dry THF (13.2 mL) solution of2-methoxy-6-(trimethylsilyl)pyridine (MTP, 1.00 g, 5.52 mmol) under anargon atmosphere at between −15° C. and 0° C. (this temperature was keptduring the reaction), stirred for 1 hour, and a dry THF (1 mL) solutionof FEO (0.868 g, 5.52×1.2 mmol) was then added dropwise and it wasstirred for 1 hour. Subsequently, n-butyllithium (1.6 M in n-hexane, 7.0mL, 5.52×2.0 mmol) was added dropwise and it was stirred for 1 hour, anda dry THF (5.5 mL) solution of iodine (3.64 g, 5.52×2.6 mmol) was thenadded dropwise and it was stirred for 30 minutes. After the temperaturewas raised to room temperature, 10% Na₂SO₃ (appropriate amount, untilthe iodine color disappeared) was added and stirred for 10 minutes, andfollowed by adding water, brine, and n-hexane (50 mL). The organic layerwas separated, dried over Na₂SO₄, filtered, and then concentrated todryness (40° C., 15 mmHg). The residue (1.80 g, yellow clear liquid) wassubjected to quantitative determination by HPLC to thus determine thecontent (59.8%) and yield (58%) of PM. The quantitative determinationand HPLC operating conditions were carried out by the same methods as inExample 1.

¹H-NMR (400 MHz, CDCl₃) δ: 0.30 (9H, s, TMS), 4.05 (3H, s, CH₃O), 7.67(1H, s, pyridine-H), 10.19 (1H, s, CHO).

IR (liquid film) (cm⁻¹): 2955, 1697 (CHO), 1551, 1512, 1331, 1250, 1022,837.

EI-MS (m/z): 335 [M]⁺, 320 (100%)

By use of the alkoxyalkylformamides [formula (I)], the same level ofyield of Example 1 was obtained at the reaction temperature of −15° C.to 0° C., which is closer to room temperature.

Example 3

It was investigated whether it was possible to introduce othersubstituents to methoxypyridine derivatives with electrophiles otherthan iodine after formylation by the alkoxyalkylformamide of the presentinvention. The reaction processes were described as follows.

Synthesis of2-methoxy-4-methyl-6-(trimethylsilyl)pyridine-3-carbaldehyde (Me-MTPC)

n-Butyllithium (1.6 M in n-hexane, 2.8 mL, 2.76×1.6 mmol) was addeddropwise to a dry THF (6.6 mL) solution of2-methoxy-6-(trimethylsilyl)pyridine (MTP, 0.500 g, 2.76 mmol) under anargon atmosphere at between −15° C. and 0° C. and stirred at the sametemperature for 1 hour, and a dry THF (3 mL) solution of FEO (0.434 g,2.76×1.2 mmol) was then added dropwise at the same temperature andstirred at the same temperature for 1 hour. Subsequently, n-butyllithium(1.6 M in n-hexane, 2.4 mL, 2.76×1.4 mmol) was added dropwise at thesame temperature and stirred at the same temperature for 2 hours, it wasthen cooled to around −70° C., and a dry THF (3 mL) solution of methyliodide (515 μL, 2.76×3.0 mmol) was added at one-portion and stirred ataround −70° C. for 1 hour. The temperature was raised to roomtemperature, followed by adding water, brine, and n-hexane (50 mL). Theorganic layer was separated, dried over Na₂SO₄, filtered, and thenconcentrated to dryness. The residue was purified by medium pressuresilica gel column chromatography (n-hexane:ethyl acetate=500:1), desiredfractions were combined and concentrated to dryness, and Me-MTPC (0.331g, 1.48 mmol, 54%) was obtained as a slightly yellow clear liquid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.30 (9H, s, TMS), 2.56 (3H, s, CH₃), 4.05(3H, s, CH₃O), 6.97 (1H, s, aromatic-H), 10.54 (1H, s, CHO).

IR (liquid film) (cm⁻¹): 2955, 1670 (CHO), 1547, 1339, 1245, 1092, 841.

EI-MS (m/z): 223 [M]⁺, 208 (100%)

Synthesis of 2-methoxy-4,6-bis(trimethylsilyl)pyridine-3-carbaldehyde(TMS-MTPC)

n-Butyllithium (1.6 M in n-hexane, 2.8 mL, 2.76×1.6 mmol) was addeddropwise to a dry THF (6.6 mL) solution of2-methoxy-6-(trimethylsilyl)pyridine (MTP, 0.500 g, 2.76 mmol) under anargon atmosphere at between −15° C. and 0° C. (this temperature was keptduring the reaction) and stirred for 1 hour, and a dry THF (2 mL)solution of FEO (0.434 g, 2.76×1.2 mmol) was then added dropwise andstirred for 1 hour. Subsequently, n-butyllithium (1.6 M in n-hexane, 2.4mL, 2.76×1.4 mmol) was added dropwise and stirred for 1 hour, and a dryTHF (3 mL) solution of chlorotrimethylsilane (697 μL, 2.76×2.0 mmol) wasthen added dropwise and stirred for 1 hour. The temperature was raisedto room temperature, followed by adding water, brine, and n-hexane (50mL). The organic layer was separated, dried over Na₂SO₄, filtered, andthen concentrated to dryness. The residue was purified by mediumpressure silica gel column chromatography (n-hexane), and desiredfractions were combined and concentrated to dryness. TMS-MTPC (0.305 g,1.08 mmol, 39%) was obtained as a colorless transparent liquid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.30 (9H, s, TMS), 0.31 (9H, s, TMS), 4.06(3H, s, CH₃O), 7.37 (1H, d, J=0.7 Hz, aromatic-H), 10.48 (1H, d, J=0.7Hz, CHO).

IR (liquid film) (cm⁻¹): 2955, 1690 (CHO), 1512, 1323, 1250, 841.

EI-MS (m/z): 281 [M]⁺, 266 (100%)

Synthesis of2-methoxy-6-trimethylsilyl-4-(methylthio)pyridine-3-carbaldehyde(MeS-MTPC)

The similar procedure and post treatments as in the synthesis of Me-MTPC(instead of methyl iodide, dimethyldisulfide, 735 μL, 2.76×3.0 mmol wasused) were carried out. The residue was purified by medium pressuresilica gel column chromatography (after impurities were eluted byn-hexane, n-hexane:ethyl acetate=500:1), desired fractions were combinedand concentrated to dryness, and MeS-MTPC (0.384 g, 1.70 mmol, 62%) wasobtained as a slightly yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.31 (9H, s, TMS), 2.44 (3H, s, MeS), 4.01(3H, s, MeO), 7.03 (1H, s, aromatic-H), 10.50 (1H, s, CHO).

IR (KBr) (cm⁻¹): 2959, 1666 (CHO), 1555, 1504, 1339, 1246, 1038, 837.

EI-MS (m/z): 255 [M]⁺, 240

Synthesis of4-chloro-2-methoxy-6-(trimethylsilyl)pyridine-3-carbaldehyde (Cl-MTPC)

The similar procedure and post treatments as in the synthesis of Me-MTPC(instead of methyl iodide, hexachloroethane, 1.96 g, 2.76×3.0 mmol wasused) were carried out. The residue was purified by medium pressuresilica gel column chromatography (n-hexane→n-hexane:ethylacetate=500:1→250:1), desired fractions were combined and concentratedto dryness, and Cl-MTPC (0.285 g, 1.17 mmol, 42%) was obtained as a paleyellow clear liquid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.31 (9H, s, TMS), 4.08 (3H, s, MeO), 7.17(1H, s, aromatic-H), 10.46 (1H, s, CHO).

IR (liquid film) (cm⁻¹): 2955, 1701 (CHO), 1562, 1531, 1339, 1250, 1034,841.

EI-MS (m/z): 245, 243 [M]⁺ (100%)

Synthesis of 4-bromo-2-methoxy-6-(trimethylsilyl)pyridine-3-carbaldehyde(Br-MTPC)

The similar procedure and post treatments as in the synthesis of Me-MTPC(instead of methyl iodide, carbon tetrabromide, 2.74 g, 2.76×3.0 mmolwas used) were carried out. The residue was purified by medium pressuresilica gel column chromatography (n-hexane:ethyl acetate 500:1), desiredfractions were combined and concentrated to dryness, and Br-MTPC (0.499g, 1.73 mmol, 63%) was obtained as a brown clear liquid.

¹H-NMR (400 MHz, CDCl₃) δ: 0.31 (9H, s, TMS), 4.07 (3H, s, MeO), 7.36(1H, s, aromatic-H), 10.37 (1H, s, CHO).

IR (liquid film) (cm⁻¹): 2955, 1701 (CHO), 1558, 1524, 1339, 1250, 1026,841.

EI-MS (m/z): 289, 287 [M]⁺, 274, 272, 197, 182 (100%)

Synthesis of 4-iodo-2-methoxypyridine-3-carbaldehyde (DeTMS-PM)

t-Butyllithium (1.5 M in n-pentane, 6.9 mL, 9.16×1.1 mmol) was addeddropwise to a dry THF (7.5 mL) solution of 2-methoxypyridine (1.00 g,9.16 mmol) between −75° C. and −60° C. and stirred at the sametemperature for 1 hour. A dry THF (10 mL) solution of FEO (1.44 g,9.16×1.2 mmol) was added dropwise at the same temperature and stirredfor 30 minutes. The temperature was raised to around −23° C., ethyleneglycol dimethyl ether (DME, organic synthesis grade, 7.5 mL) was added,and subsequently n-butyllithium (1.6 M in n-hexane, 9.9 mL, 9.16×1.7mmol) was added dropwise at between −15° C. and −25° C. and stirred ataround −23° C. for 2 hours. The mixture was cooled to around −70° C., aDME (10 mL) solution of iodine (4.42 g, 9.16×1.9 mmol) was added atone-portion, and stirred at around −70° C. for 30 minutes. Thetemperature was raised to room temperature, 10% Na₂SO₃ (appropriateamount, until the iodine color disappeared) was added and it was stirredfor 10 minutes, followed by adding water, brine, and ethyl acetate (50mL). The organic layer was separated, dried over Na₂SO₄, filtered, andthen concentrated to dryness. The residue (brown solid) was dissolved inchloroform and purified by medium pressure silica gel columnchromatography (n-hexane:ethyl acetate=1000:1→100:1). Desired fractionswere concentrated to dryness, and DeTMS-PM (1.31 g, 4.98 mmol, 54%) wasobtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 4.05 (3H, s, MeO), 7.54 (1H, d, J=5.4 Hz,aromatic-H), 7.85 (1H, d, J=5.4 Hz, aromatic-H), 10.21 (1H, s, CHO).

IR (KBr) (cm⁻¹): 2943, 1697 (CHO), 1543, 1458, 1362, 1015.

EI-MS (m/z): 263 [M]⁺ (100%)

Synthesis of 6-chloro-4-iodo-2-methoxypyridine-3-carbaldehyde (6Cl-PM)

t-Butyllithium (1.5 M in n-pentane, 5.2 mL, 6.97×1.1 mmol) was addeddropwise to a dry THF (7.5 mL) solution of 6-chloro-2-methoxypyridine(1.00 g, 6.97 mmol) at between −75° C. and −60° C. and stirred at thesame temperature for 1 hour. A dry THF (10 mL) solution of FEO (1.10 g,6.97×1.2 mmol) was added dropwise at the same temperature and stirredfor 30 minutes. The temperature was raised to around −23° C., ethyleneglycol dimethyl ether (DME, organic synthesis grade, 7.5 mL) was added,and subsequently n-butyllithium (1.6 M in n-hexane, 7.5 mL, 6.97×1.7mmol) was added dropwise at between −150° C. and −25° C. and stirred ataround −23° C. for 2 hours. The mixture was cooled to around −70° C.,and a DME (10 mL) solution of iodine (3.36 g, 6.97×1.9 mmol) was addedat one-portion and stirred at around −70° C. for 30 minutes. Thetemperature was raised to room temperature, 10% Na₂SO₃ (appropriateamount, until the iodine color disappeared) was added and it was stirredfor 10 minutes, followed by adding water, brine, and ethyl acetate (50mL). The organic layer was separated, dried over Na₂SO₄, filtered, andthen concentrated to dryness. The residue (brown solid) was dissolved inchloroform and purified by medium pressure silica gel columnchromatography (n-hexane:ethyl acetate=500:1). Desired fractions wereconcentrated to dryness, and 6Cl-PM (1.17 g, 3.95 mmol, 57%) wasobtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 4.07 (3H, s, MeO), 7.58 (1H, d, J=0.5 Hz,aromatic-H), 10.16 (1H, d, J=0.5 Hz, CHO).

IR (KBr) (cm⁻¹): 2951, 1690 (CHO), 1539, 1350, 1261, 1007.

EI-MS (m/z): 299, 297 [M]⁺ (100%)

It was possible to introduce an alkyl group, a silyl group, anotherhalogen, a sulfur atom and the like into the 4 position (R′) of thepyridine ring.

In case that synthesis of other substrates known as syntheticintermediates for the CPT skeleton (R═H, R′═I, and R═Cl, R′═I) wascarried out, the targets were obtained in a similar yield to that in thesynthesis of compound (b).

From the above results, it has been shown that alkoxyalkylformamides[formula (I)] have the versatile ability for formylation andsubstitution at the ortho position to the formyl group.

Example 4

In the step of obtaining compound (d) from compound (c), the exo form(d′) is formed as a by-product. For the purpose of improving theendo:exo product ratio, the reaction conditions were investigated indetail.

Compound (c) (0.30 g, 0.767 mmol) was dissolved in a solvent (6.1 mL)shown in Table 3, N,N-diisopropylethylamine (1.04 mL, 6.14 mmol, 8.0eq.) and palladium acetate (17 mg, 0.077 mmol) were added at roomtemperature while adding or not adding tetrabutylammonium bromide (0.25g, 0.767 mmol), and it was heated under reflux. The reaction mixture wascooled to room temperature, 10% Na₂SO₃ (4.8 mL) and n-hexane (50 mL)were added, and the organic layers (among 3 layers, upper and middlelayers) were then collected. The organic layers were further washed with1 N HCl (6.1 mL) and subsequently with water (20 mL×2), and it was thendried over anhydrous Na₂SO₄, filtered, and concentrated to dryness underreduced pressure. The residue was analyzed by HPLC, and the endo/exoratio and the yield were determined. The yield and the endo/exo ratioare given in Table 3.

¹H-NMR (400 MHz, CDCl₃) δ: 0.26 (9H, s, TMS), 1.12 (3H, t, J=7.3 Hz,CH₂CH₃), 2.31 (2H, dq, J=1.0, 7.3 Hz, CH₂CH₃), 3.94 (3H, s, OCH₃), 5.00(2H, s, OCH₂), 6.51 (1H, t, J=1.0 Hz, OCH═), 6.83 (1H, s, pyridine-H).

IR (liquid film) (cm⁻¹): 2963, 1634, 1583, 1342, 835.

EI-MS (m/z): 263 [M⁺], 248 (100%)

Conditions for determination of geometric isomer ratio of compound d(HPLC)Detector: UV absorptiometer (254 nm)

Column: Inertsil ODS-2, 5 μm, 4.6 mm I.D.×250 mm

Column temperature: constant temperature at around 40° C.Mobile phase: acetonitrile/0.01 mol/L potassium dihydrogen phosphatemixture (5:1)Flow rate: about 1 mL/minArea measurement range: about 50 minutesInjection volume: 10 μL, 10 mg/10 mL (acetonitrile)

Quantitative Determination Method for Compound d

About 20 mg of a test sample was precisely weighed and dissolved inacetonitrile to accurately make 50 mL, thus giving a sample solution.About 20 mg of standard compound (d) (column purified product: knownpurity) was precisely weighed and dissolved in acetonitrile toaccurately make 50 mL, thus giving a standard solution. 10 μL of each ofthe sample and the standard solution were tested by a liquidchromatographic method in accordance with a Japanese PharmacopeiaGeneral Test Procedure under the operating conditions for determinationof the geometric isomer ratio of compound (d). The peak areas ofcompound (d) obtained from the sample and from the standard solutionwere measured and the content was determined by the formula below.

Content (%) of compound (d)=At×Ws×P/(As×Wt)

At: peak area of compound d obtained from sample solution

As: peak area of compound d obtained from standard solution

Wt: sampling weight of test compound (d) (mg)

Ws: sampling weight of standard compound (d) (mg)

P: purity of standard compound (d) (%)

TABLE 3 nBu₄NBr Reaction Run Solvent (eq.) time (h) endo:exo¹⁾ Yield²⁾(%) 1 IPE-MeCN (4:3) 0 47  8.5:1 47 (28) 2 IPE-MeCN (4:3) 1 45 17.2:1 873 THF-MeCN (4:3) 1 9 17.9:1 87 4 IPE-H₂O (9:1) 1 72  9.4:1 27 (53) 5MeCN-H₂O (9:1) 1 0.5 10.4:1 82 6 THF-H₂O (9:1) 1 0.5 12.4:1 92 7IPE-DMF-H₂O (4:3:1) 1 6  4.3:1 78 8 DME-MeCN-H₂O (4:3:1) 1 0.5 11.4:1 899 IPE-THF-H₂O (4:3:1) 1 1.5 11.5:1 85 10 THF-MeCN-H₂O (4:3:1) 1 0.513.8:1 88 11 ET₂0-MeCN-H₂O (4:3:1) 1 1 18.6:1 85 12 IPE-EtCN-H₂O (4:3:1)1 0.5 17.6:I 88 13 CHCl₃-MeCN-H₂O (4:3:1) 1 29 24.7:1 55 14 IPE-MeCN-H₂O(4:3:1) 0 20 14.9:1 83 15 IPE-MeCN-H₂O (4:3:1) 1 0.5-2 15.1-17.8:1 85-91¹⁾Ratio obtained by correcting HPLC area using peak intensity (254 nm).²⁾Endo form, quantitatively determined by HPLC. Figure in parentheses isrecovery yield of compound ^((c))(HPLC area %)

In case that the quaternary ammonium salt was present, the reaction wasaccelerated, and the product ratio was also improved (run 1 vs run 2,and run 14 vs run 15).

The presence of water was also effective in promoting the reaction (run2 vs run 15, and run 3 vs run 10).

With regard to the organic solvent, in case that ether-type andnitrile-type solvents were combined (runs 10, 11, 12, and 15), theselectivity improved remarkably and the yield was favorable comparedwith cases where they were used on their own (runs 4, 5, and 6) or inother combinations (runs 7 and 9).

The chloroform-acetonitrile-water mixture gave a favorable endo:exoratio, but other impurities were formed as by-products, and the yieldwas moderate.

Example 5

The solvent ratio (IPE-MeCN-water) was then examined. The reactionconditions were the same as in Example 4. The results are given in Table4; in case that the solvent ratio was changed, there was no great changein the endo/exo ratio. Therefore a reaction at various solvent ratioswas possible.

TABLE 4 IPE-MeCN—H₂O Reaction Yield Run Ratio time (h) Endo:exo¹⁾ (%)²⁾1 6:1:1 1 13.5:1 88 2 5:2:1 2 14.8:1 80 3 4.5:2.5:1 2 15.6:1 83 43.5:3.5:1 2 14.6:1 86 5 3:4:1 0.5 15.1:1 90 6 1:6:1 0.5 14.6:1 81 ¹Ratioobtained by correcting HPLC area using peak intensity (254 nm). ²Endoform, quantitatively determined by HPLC.

Example 6

An experiment was next carried out by changing the solvent, catalyst,and base.

Compound (c) (0.30 g, 0.767 mmol) was dissolved in a solvent (6.1 mL)shown in Table 5, tetrabutylammonium bromide (0.25 g, 0.767 mmol), abase (6.14 mmol), and a catalyst (0.077 mmol) were added at roomtemperature, and it was heated under reflux. The reaction mixture wascooled to room temperature and filtered, 10% Na₂SO₃ (4.8 mL) andn-hexane (50 mL) were added to the solution, and the organic layers(among 3 layers, upper and middle layers) were then collected. Theorganic layers were further washed with 1 N HCl (6.1 mL) andsubsequently with water (20 mL×2), and it was then dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness under reduced pressure.The residue was analyzed by HPLC, and the endo/exo ratio and yield weredetermined. The results are given in Table 5. In case that the solventwas an acetonitrile-water mixture, the catalyst was palladium (II)chloride, and the base was triethylamine, gave very favorable results(run 8) for both the yield (93%) and the endo/exo ratio (29.3:1). Theendo/exo ratio was corrected by the HPLC peak intensity ratio (254 nm).

TABLE 5 Catalyst Time Yield Run Solvent 10 mol % Base 8 eq. h %endo:exo^(e)) 1 MeCN Pd(OAc)₂ i-Pr₂NEt 3 79 10.9:1.0 2 MeCN-H₂O^(a)) ″ ″1 82 10.4:1.0 3 IPE-H₂O^(a)) ″ ″ 72 27  9.4:1.0 4 IPE-MeCN^(b)) ″ ″ 4587 17.2:1.0 5 IPE-MeCN- ″ ″ 1 90 17.8:1.0 H₂O^(c)) 6 IPE-MeCN- ″ Et₃N 187 19.2:1.0 H₂O^(c)) 7 IPE-MeCN- PdCl₂ ″ 1 95 26.4:1.0 H₂O^(c)) 8MeCN-H₂O^(d)) ″ ″ 1 93 29.8:1.0 Ref. DMF Pd(OAc)₂ K₂CO₃ ^(f)) 1 69 4.3:1.0 Ex. temp.) reflux ^(a))9:1 ^(b))4:3 ^(c))4:3:1 ^(d))7:1^(e))HPLC (corrected by peak intensity ratio) ^(f))4 eq.

Example 7

An experiment was next carried out by changing the catalyst and thebase.

Compound (c) (0.30 g, 0.767 mmol) was dissolved in a diisopropylether-acetonitrile-water mixture (4:3:1, 6.1 mL), tetrabutylammoniumbromide (0.25 g, 0.767 mmol), triethylamine (0.85 mL, 6.14 mmol, 8 eq.)or potassium carbonate (0.212 g, 1.53 mmol, 4 eq), and a catalyst shownin Table 5 (0.077 mmol) were added at room temperature, and it washeated under reflux. The reaction mixture was cooled to room temperatureand filtered, 10% Na₂SO₃ (4.8 mL) and n-hexane (50 mL) were added, andthe organic layers (among 3 layers, upper and middle layers) were thencollected. The organic layers were further washed with 1 N HCl (6.1 mL)and subsequently water (20 mL×2), dried with anhydrous Na₂SO₄, filtered,and concentrated to dryness under reduced pressure. The residue wasanalyzed by HPLC, and the endo/exo ratio and yield were determined. Theresults are given in Table 6.

TABLE 6 Reaction Yield Run Catalyst Base time (h) endo:exo¹⁾ (%)²⁾ 1Pd(OAc)₂ Et₃N 1 19.2:1 87 2 Pd(OAc)₂ K₂CO₃ 40 10.2:1 47 (33) 3 (Ph₃P)₄PdEt₃N 119    1:11.1 — (41) 4 (Ph₃P)₂PdCl₂ Et₃N 0.5   1:2.1 40 5 PdCl₂Et₃N 0.5 26.4:1 95 6 (MeCN)₂PdCl₂ Et₃N 1 25.8:1 95 7 (PhCN)₂PdCl₂ Et₃N 127.0:1 93 8 (dba)₂Pd Et₃N 5 25.6:1 87 9 [(allyl)PdCl]₂ Et₃N 91 18.5:1 50(36) 10 (dppf)PdCl₂ Et₃N 1   1:1.3 50 11 20% Pd(OH)₂—C Et₃N 70 16.9:1 8812 10% Pd—C Et₃N 15 16.9:1 79 ¹⁾Ratio obtained by correcting HPLC areausing peak intensity (254 nm). ²⁾Endo form, figure in parentheses isrecovery yield of compound (c) (HPLC area %)

The use of triethylamine as the base improved the endo:exo ratio (run 15in Table 3 vs run 1 in Table 6). The catalysts of runs 5 to 8 furtherimproved the selectivity, and compound (d) was obtained in good yield.

As described above, by use of an ether-type—water mixture or anether-type—nitrile-type—water mixture as the solvent, triethylamine asthe base, and palladium (II) chloride, palladium (II) acetate,palladium-carbon, palladium hydroxide-carbon, bis(acetonitrile)palladium(II) chloride, bis(benzonitrile)palladium (II) chloride, orbis(dibenzylideneacetone)palladium (0) as the catalyst in the presenceof a quaternary ammonium salt, compound (d) is obtained with a betterendo:exo ratio and yield than a reference example in [Table 5] underknown literature conditions.

Reference Example

It has been reported that the use of a Wilkinson complex in anintramolecular Heck reaction of a compound (C) analog improves theendo:exo ratio (Bankston, D.; Fang, F.; Huie, E.; Xie, S., J. Org. Chem.1999, 64, 3461-3466). Although the reported conditions were applied tocompound (C) (run 1) and reaction conditions such as the amount ofWilkinson complex added were examined, no improvement in the endo/exoratio or the yield was observed.

TABLE 7 nBu₄NX Catalyst²⁾ Additive³⁾ Base X (mol Temp.⁴⁾ Run Solvent¹⁾mol % mol % mol times times) ° C. Time h endo:exo⁵⁾ Yield⁶⁾ % 1-1 DMF2.3 A (0.8) K₂CO₃ (2) Cl (0.5) 21→85 47 7.2:1 63 1-2 DMF 2.3 A (0.8)K₂CO₃ (2) Cl (0.5) 24→90 21 8.1:1 55 3 I-M-H 10 A (3.3) K₂CO₃ (2) Br (1)24→90 1.5 4.8:1 69 4 I-M-H 10 A (3.3) iPr₂NEt (8) Br (1) 21→reflux 1  1:1.1 55 ¹⁾I-M-H = IPE-MeCN-water(4:3:1) ²⁾Pd(OAc)₂ ³⁾A = (Ph₃P)₃RhCl,B = RhCl₃H₂0 ⁴⁾(Temp reagent added)→(Reaction temp) ⁵⁾Ratio obtained bycorrecting HPLC area using peak intensity (254 nm) ⁶⁾Endo form

Processes for preparation and analytical methods of the compounds usedin the Examples above are illustrated below.

Synthesis of N-ethoxyethyl-N-methylbenzylamine (BnEO)

Process 1) NaH (washed with hexane in advance, 8.78 g, 0.305×1.2 mol)was added to a dry THF (300 mL) solution of N-methylbenzylamine (39 mL,0.305 mol) under an argon atmosphere at room temperature. After stirringat room temperature for 30 minutes, a dry THF (100 mL) solution ofbromoethyl ethyl ether (51 mL, 0.305×1.5 mol) was added dropwise, andfurther heated under reflux under an argon atmosphere for 24 hours.After cooling to room temperature, water (350 mL) was carefully addedfor dissolution of insoluble materials, followed by adding ethyl acetate(350 mL). The organic layer was separated, further washed with brine(200 mL) and then concentrated to dryness. Since insoluble materialsprecipitated in the residual fraction, they were filtered off and washedwith ethyl acetate, and the filtrate was again concentrated to dryness.The residue was purified by vacuum distillation (fraction at 1.0 to 1.1kpa and 95° C. to 110° C. collected), and BnEO (49.73 g, 0.257 mol, 84%)was obtained as a colorless transparent liquid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.21 (3H, t, J=7.1 Hz, CH₃), 2.27 (3H, s,CH₃), 2.62 (2H, t, J=6.1 Hz, CH₂), 3.49 (2H, quar., J=7.1 Hz, CH₂), 3.57(2H, s, CH₂), 3.57 (2H, t, J=6.1 Hz, CH₂), 7.22 to 7.34 (5H, m,aromatic-H).

IR (liquid film) (cm⁻¹): 3028, 2866, 1454, 1111 (ether), 737(monosubstituted benzene), 698 (monosubstituted benzene).

EI-MS (m/z): 193 [M]⁺, 134 (100%)

Process 2) Bromoethyl ethyl ether (1.3 mL, 7.76×1.3 mmol) was added to amethanol (5 mL) solution of N-methylbenzylamine (1.0 mL, 7.76 mmol) atroom temperature, and heated under reflux for 18 hours. After cooling toroom temperature, the residue obtained by concentration to dryness wasmixed with water and saturated NaHCO₃ to make it basic (pH paper), andextracted with chloroform (2 times). The combined organic layers weredried over anhydrous Na₂SO₄, filtered, and subsequently concentrated todryness. The residue was purified by medium pressure silica gel columnchromatography (n-hexane:ethyl acetate=4:1), a target fraction wasconcentrated to dryness, and BnEO (0.907 g, 4.69 mmol, 61%) was obtainedas a pale yellow clear liquid.

Synthesis of N-ethoxyethyl-N-methylformamide (FEO)

10% Pd—C (manufactured by Kawaken Fine Chemicals, Co. Ltd., M, Dry,moisture content 1.7%, 2.24 g) and formic acid (43 mL, 0.223×5 mol) wereadded to a methanol (430 mL) solution of BnEO (43.11 g, 0.223 mol) underan argon atmosphere and it was heated under reflux for 90 minutes. Aftercooling to room temperature, the Pd—C was removed by filtration with apad of Celite, washed with methanol, and the filtrate was concentratedto dryness. Toluene (430 mL) was added to the residue and heated underreflux for 20 hours while removing water formed as a by-product with aDean-Stark tube. After cooling to room temperature, K₂CO₃ (90 g, 0.223×3mol) was added and it was stirred at room temperature for 3 hours.Insoluble materials were removed by filtration, washed with toluene, andthe filtrate was then concentrated to dryness. The residue was purifiedby vacuum distillation with a Vigreux fractionating column (15 cm)(fraction at 0.5 to 0.7 kpa, 78° C. to 80° C. collected), and FEO (24.36g, 0.186 mol, 83%) was obtained as a colorless transparent liquid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.18, 1.19 (3H, each t, each J=7.1 Hz, CH₃),2.92, 3.04 (3H, each s, CH₃), 3.36 to 3.57 (6H, m, CH₂×3), 8.06 (1H, s,CHO).

IR (liquid film) (cm⁻¹): 2974, 2866, 1678 (CHO), 1396, 1119 (ether).

EI-MS (m/z): 131[M⁺], 85, 72 (100%).

Synthesis of N-methoxyethyl-N-methylbenzylamine (BnMO)

The synthesis of BnMO was carried out in a manner similar to that ofBnEO (process 2) using N-methylbenzylamine (15 mL, 0.116 mol),bromoethyl methyl ether (12 mL, 0.116×1.1 mmol), and ethanol (200 mL) asa solvent. BnMO (12.09 g, 67.46 mmol, yield 58%) was obtained as a paleyellow clear liquid.

[Purification was Carried Out by Medium Pressure Silica Gel Column(Ethyl Acetate).]

¹H-NMR (400 MHz, CDCl₃) δ: 2.27 (3H, s, CH₃), 2.61 (2H, t, J=5.9 Hz,CH₂), 3.34 (3H, s, CH₃), 3.52 (2H, t, J=5.9 Hz, CH₂), 3.56 (2H, s, CH₂),7.22 to 7.33 (5H, m, aromatic-H).

IR (liquid film) (cm⁻¹): 3028, 2874, 1454, 1119 (ether), 737(monosubstituted benzene), 698 (monosubstituted benzene).

EI-MS (m/z):179[M]⁺, 134, 91 (100%)

Synthesis of N-methoxyethyl-N-methylformamide (FMO)

The synthesis of FMO was carried out in a manner similar to that of FEOusing BnMO (10.00 g, 55.79 mmol). FMO (3.60 g, 30.70 mmol, yield 55%)was obtained as a colorless transparent liquid. (In a purification byvacuum distillation, a fraction at 4.2 kpa, 47° C. to 54° C. wascollected.)

¹H-NMR (400 MHz, CDCl₃) δ: 2.86, 2.98 (3H, each s, CH₃), 3.00, 3.00 (3H,each s, CH₃), 3.34 to 3.52 (4H, m, CH₂CH₂), 8.00, 8.01 (1H, each s,CHO).

IR (liquid film) (cm⁻¹): 2928, 2878, 1674 (CHO), 1396, 1119 (ether).

EI-MS (m/z): 117[M]⁺, 85, 72 (100%)

Synthesis of N-ethyl-N-methoxyethylbenzylamine (BnEA)

The synthesis of BnEA was carried out in a manner similar to that ofBnEO (process 2) using N-ethylbenzylamine (15 mL, 0.101 mol), bromoethylmethyl ether (0.101×1.2 mol), and ethanol (100 mL) as a solvent. BnEA(9.17 g, 47.46 mmol, yield 47%) was obtained as a yellow-orange clearliquid. [Purification was carried out by medium pressure silica gelcolumn chromatography (n-hexane:ethyl acetate=3:2).]

¹H-NMR (400 MHz, CDCl₃) δ: 1.07 (3H, t, J=7.1 Hz, CH₃), 2.59 (2H, quar.,J=7.1 Hz, CH₂), 2.68 (2H, t, J=6.3 Hz, CH₂), 3.33 (3H, s, CH₃), 3.48(2H, t, J=6.3 Hz, CH₂), 3.65 (2H, s, CH₂), 7.22 to 7.38 (5H, m,aromatic-H).

IR (liquid film) (cm⁻¹): 3028, 2970, 2812, 1454, 1123 (ether), 733(monosubstituted benzene), 698 (monosubstituted benzene).

EI-MS (m/z): 193 [M]⁺, 148 (100%)

Synthesis of N-ethyl-N-methoxyethylformamide (FEA)

The synthesis of FEA was carried out in a manner similar to that of FEOusing BnEA (5.57 g, 28.82 mmol). FEA (2.45 g, 18.66 mmol, yield 65%) wasobtained as a colorless transparent liquid. (In a purification by vacuumdistillation, a fraction at 0.9 to 1.0 kpa, 85° C. to 86° C. wascollected.)

¹H-NMR (400 MHz, CDCl₃) δ: 1.14, 1.19 (3H, each t, each J=7.1 Hz, CH₃),3.34, 3.35 (3H, each s, CH₃), 3.37 to 3.55 (6H, m, CH₂×3), 8.03, 8.10(5H, m, aromatic-H).

IR (liquid film) (cm⁻¹): 2936, 2878, 1670 (CHO), 1431, 1119 (ether).

EI-MS (m/z): 131[M]⁺, 99, 86 (100%)

Synthesis of N-ethoxyethyl-N-ethylbenzylamine (BnEE)

The synthesis of FEA was carried out in a manner similar to that of BnEO(process 2) using N-ethylbenzylamine (15 mL, 0.101 mol), bromoethylethyl ether (17 mL, 0.101×1.5 mol), and ethanol (100 mL) as a solvent.BnEE (12.79 g, 61.69 mmol, yield 61%) was obtained as a pale yellowclear liquid. [Purification was carried out by medium pressure silicagel column chromatography (ethyl acetate:n-hexane=4:1).]

¹H-NMR (400 MHz, CDCl₃) δ: 1.08 (3H, t, J=7.1 Hz, CH₃), 1.21 (3H, t,J=7.1 Hz, CH₃), 2.61 (2H, quar., J=7.1 Hz, CH₂), 2.71 (2H, t, J=6.6 Hz,CH₂), 3.49 (2H, quar., J=7.1 Hz, CH₂), 3.54 (2H, t, J=6.6 Hz, CH₂), 3.67(2H, s, CH₂), 7.24 to 7.38 (5H, m, aromatic-H).

IR (liquid film) (cm⁻¹): 3028, 2970, 1454, 1115 (ether), 733(monosubstituted benzene), 698 (monosubstituted benzene).

EI-MS (m/z): 207[M]⁺, 148 (100%)

Synthesis of N-ethoxyethyl-N-ethylformamide (FEE)

The synthesis of FEE was carried out in a manner similar to that of FEOusing BnEE (10.00 g, 48.23 mmol). FEE (4.80 g, 33.03 mmol, yield 68%)was obtained as a colorless transparent liquid. (In a purification byvacuum distillation, a fraction at 0.8 to 0.9 kpa, 91° C. to 92° C. wascollected.)

¹H-NMR (400 MHz, CDCl₃) δ: 1.13, 1.17, 1.17, 1.19 (6H, each t, J=7.1 Hz,CH₃×2), 3.34 to 3.56 (8H, m, CH₂×4), 8.03, 8.09 (1H, each s, CHO).

IR (liquid film) (cm⁻¹): 2974, 2870, 1674 (CHO), 1431, 1119 (ether).

EI-MS (m/z): 145 [M]⁺, 99, 86 (100%)

Synthesis of N-methoxymethyl-N-methylformamide (FMM)

NaH (washed with n-hexane in advance, 6.71 g, 0.254×1.1 mol) was addedto a dry THF (150 mL) solution of N-methylformamide (15.00 g, 0.254 mol)under an argon atmosphere with ice-bath cooling, and stirred for 30minutes. A dry THF (20 mL) solution of chloromethyl methyl ether (24.54g, 0.254×1.2 mol) was added dropwise under an argon atmosphere at thesame temperature and then stirred for 2 hours, and further stirred atroom temperature for 3 hours. After cooling with ice-bath, n-hexane (100mL) was added to the reaction mixture and it was stirred for 1 hour, andinsoluble materials were then removed by filtration with a pad ofCelite. A residue obtained by concentrating the filtrate to dryness (40°C., 15 mmHg) was purified by vacuum distillation (fraction at 1.6 kpa,66° C. to 68° C. collected), and FMM (7.90 g, 76.61 mmol, 30%) wasobtained as a colorless transparent liquid.

¹H-NMR (400 MHz, CDCl₃) δ: 2.92, 2.98 (3H, each s, CH₃), 3.25, 3.29 (3H,each s, CH₃), 4.63, 4.77 (2H, each s, CH₂), 8.19 (1H, s, CHO).

IR (liquid film) (cm⁻¹): 2936, 1674 (CHO), 1400, 1099 (ether).

EI-MS (m/z): 103 [M]⁺, 88 (100%)

Synthesis of N-ethoxypropyl-N-methylformamide (FEP)

Formic acid (9.4 mL, 0.208×1.2 mol) was added to a toluene (250 mL)solution of 3-ethoxypropylamine (25 mL, 0.208 mol) at room temperature,and heated under reflux for 17 hours while removing water formed as aby-product with a Dean-Stark tube. After cooling to room temperature,K₂CO₃ (14 g, 0.208×0.5 mol) was added and it was stirred for 90 minutes.Insoluble materials were removed by filtration, washed with toluene, andthe filtrate was concentrated to dryness. The residue was purified byvacuum distillation with a Vigreux fractionating column (15 cm)(fraction at 0.6 kpa, 114° C. to 115° C. collected), andN-(3-ethoxypropyl)formamide (21.79 g, 0.166 mol, 80%) was obtained as acolorless transparent liquid.

NaH (washed with n-hexane in advance, 2.01 g, 76.24×1.1 mmol) was addedto a dry THF (100 mL) solution of N-(3-ethoxypropyl)formamide (10.00 g,76.24 mmol) under an argon atmosphere with ice-bath cooling, and stirredfor 30 minutes. A dry THF (10 mL) solution of methyl iodide (5.7 mL,76.24×1.2 mmol) was added dropwise to the reaction mixture under anargon atmosphere with ice-bath cooling, it was then stirred for 30minutes, and further stirred at room temperature for 90 minutes. NaH(washed with n-hexane in advance, 0.20 g, 76.24×0.1 mmol) was againadded and it was stirred at room temperature for 1 hour. After coolingwith ice-bath, n-hexane (100 mL) was added to the reaction mixture andit was stirred for 1 hour, and insoluble materials were then removed byfiltration with a pad of Celite. A residue obtained by concentrating thefiltrate to dryness was purified by vacuum distillation (fraction at 0.6kpa, 91° C. collected), and FEP (4.17 g, 28.68 mmol, 38%) was obtainedas a pale yellow clear liquid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.19, 1.20 (3H, each t, each J=7.1 Hz, CH₃),1.78 to 2.30 (2H, m, CH₂), 2.86, 2.96 (3H, each s, CH₃), 3.45 to 3.50(6H, m, CH₂×3), 8.03, 8.09 (1H, each s, CHO).

IR (liquid film) (cm⁻¹): 2932, 2862, 1678 (CHO), 1397, 1111 (ether).

EI-MS (m/z): 145 [M]⁺, 116, 101, 72 (100%)

INDUSTRIAL APPLICABILITY

By use of the synthetic process of the present invention, highly puretricyclic ketones can be synthesized in a short period of time, and byuse of these intermediates, a total synthesis of CPT analogs can beaccomplished efficiently and practically.

1. A process for preparing a tricyclic ketone (k), represented by theformula below, for synthesizing camptothecin analogs

(wherein Me denotes a methyl group, Pr denotes a propyl group, and t-Budenotes a t-butyl group), the process comprising a step (1) of mixingthe above compound (a), a compound represented by formula (I)

(wherein R and R′ are independently alkyl having 1 or 2 carbons, and nis an integer of 1 to 3) and a lithiation reagent, and subsequentlymixing with an iodination reagent to give compound (b).
 2. The processfor preparing the tricyclic ketone (k) according to claim 1, furthercomprising a step (2) of mixing and stirring in a solvent at least onetype of palladium catalyst selected from palladium (II) chloride,palladium (II) acetate, palladium-carbon, palladium hydroxide-carbon,bis(acetonitrile)palladium (II) dichloride, bis(benzonitrile)palladium(II) dichloride, and bis(dibenzylideneacetone)palladium (0), compound(c), a base, and a quaternary ammonium salt to give compound (d).
 3. Theprocess for preparing the tricyclic ketone (k) according to claim 1,wherein in step (1) the compound represented by formula (I) in which nis 2 is used.
 4. The process for preparing the tricyclic ketone (k)according to claim 1, wherein in step (1) the lithiation reagent isn-butyllithium.
 5. The process for preparing the tricyclic ketone (k)according to claim 2, wherein in step (2) the solvent is awater-containing solvent.
 6. The process for preparing the tricyclicketone (k) according to claim 2, wherein in step (2) the solvent is amixture of a nitrile-type organic solvent and water.
 7. The process forpreparing the tricyclic ketone (k) according to claim 2, wherein in step(2) the solvent is a mixture of an ether-type organic solvent, anitrile-type organic solvent, and water.
 8. A method for preparation ofcamptothecin analogs comprising reacting the tricyclic ketone (k)obtained by the process of claim
 1. 9. A process for synthesizingcamptothecin analogs, the process involving reacting the tricyclicketone (k) obtained by the process according to claim 1 with2′-amino-5′-hydroxypropiophenone.
 10. A process for preparing aformylated methoxypyridine derivative by reacting a methoxypyridinederivative with a compound (alkoxyalkylformamide) represented by formula(I)

(wherein R and R′ are independently alkyl having 1 or 2 carbons, and nis an integer of 1 to 3).
 11. The process for preparing a formylatedmethoxypyridine derivative according to claim 10, wherein a compoundrepresented by formula (I) in which n is 2 is used.
 12. The process forpreparing a formylated methoxypyridine derivative according to claim 10,wherein it is carried out in the presence of n-butyllithium.
 13. Aprocess for preparing a formylated methoxypyridine derivative, whereinit is a process for preparing a compound represented by formula (II)

(wherein R is a halogen, alkyl, or trimethylsilyl group, and R′ is ahalogen, alkyl, trimethylsilyl, or thioalkyl group), and an orthoposition to a formyl group introduced by the preparation processaccording to claim 10 is substituted with an electrophile.
 14. Analkoxyalkylformamide represented by formula (I)

(wherein R and R′ are independently alkyl having 1 or 2 carbons and n isan integer of 1 to 3, but excluding one in which n is 1 and R and R′ areboth methyl, one in which R is methyl and R′ is ethyl and one in which nis 2 and R and R′ are both ethyl).
 15. The process for preparing thetricyclic ketone (k) according to claim 2, wherein in step (1) thecompound represented by formula (I) in which n is 2 is used.
 16. Theprocess for preparing the tricyclic ketone (k) according to claim 2,wherein in step (1) the lithiation reagent is n-butyllithium.
 17. Theprocess for preparing the tricyclic ketone (k) according to claim 3,wherein in step (1) the lithiation reagent is n-butyllithium.
 18. Amethod for preparation of camptothecin analogs comprising reacting thetricyclic ketone (k) obtained by the process of claim
 2. 19. A processfor synthesizing camptothecin analogs, the process involving reactingthe tricyclic ketone (k) obtained by the process according to claim 2with 2′-amino-5′-hydroxypropiophenone.
 20. The process for preparing aformylated methoxypyridine derivative according to claim 11, wherein itis carried out in the presence of n-butyllithium.
 21. A process forpreparing a formylated methoxypyridine derivative, wherein it is aprocess for preparing a compound represented by formula (II)

(wherein R is a halogen, alkyl, or trimethylsilyl group, and R′is ahalogen, alkyl, trimethylsilyl, or thioalkyl group), and an orthoposition to a formyl group introduced by the preparation processaccording to claim 11 is substituted with an electrophile.
 22. A processfor preparing a formylated methoxypyridine derivative, wherein it is aprocess for preparing a compound represented by formula (II)

(wherein R is a halogen, alkyl, or trimethylsilyl group, and R′ is ahalogen, alkyl, trimethylsilyl, or thioalkyl group), and an orthoposition to a formyl group introduced by the preparation processaccording to claim 12 is substituted with an electrophile.